In this NIH R15 proposal we outline the development of sequential catalytic asymmetric ketene heterodimerization-reduction processes to provide stereodefined deoxypropionates suitable for natural product synthesis. The importance of deoxypropionate containing polyketides stems from the fact that they have a broad range of biological activities, e.g. as cytostatics (e.g. borrelidin and doliculide), or as potential conduis for tuberculosis therapy (as drug targets or vaccines). We recently reported that a catalytic asymmetric ketene heterodimerization could be accomplished through a stepwise mechanism promoted by an alkaloid nucleophilic catalytic system. 17 examples of ketene heterodimer -lactones were prepared in 90% ee. Diastereoselective hydrogenolysis of the ketene heterodimers obtained would provide access to carboxylic acids bearing two chiral centers (deoxypropionate units) as the anti-deoxypropionate. An alternative approach would involve the asymmetric synthesis of a -lactone through catalytic hydrogenation of a ketene heterodimer, followed by SN2 ring-opening of the -lactone by a hydride reagent to provide access to the syn-deoxypropionate. The proposed sequential catalytic ketene heterodimerization-reduction sequences would therefore provide powerful and complementary asymmetric methods for deoxypolypropionate construction. Such methods possess great potential because deoxypolypropionates are frequently investigated as therapeutic agents for tuberculosis and cancer. The synthetic utility of the proposed methodologies will be validated through application to the synthesis of two biologically important deoxypropionate molecules, mycocerosic acid and (-)-mycolipanolic acid, which we expect to be assembled in significantly fewer steps than has previously been possible. Our specific aims for this NIH R15 AREA proposal are as follows: 1. Specific Aim no.1: To explore catalytic hydrogenolysis of ketene heterodimers for the synthesis of anti-deoxypropionates 2. Specific Aim no.2: To explore catalytic hydrogenation of ketene heterodimers for the synthesis of -lactones bearing three chiral centers. 3. Specific Aim no.3: To explore hydride-mediated SN2 ring-opening of -lactones for the synthesis of syn-deoxypropionate derivatives. 4. Specific Aim no.4: To investigate the utility of ketene heterodimer-derived deoxypropionates in the asymmetric synthesis of mycocerosic acid. 5. Specific Aim no.4: To investigate the utility of ketene heterodimer-derived deoxypropionates in the asymmetric synthesis of (-)-mycolipanolic acid.